The purpose of this competing renewal focuses on liver disease in HIV-HBV (hepatitis B virus) co- infected individuals receiving HBV-active antiretroviral therapy. In broad terms, the goals include optimizing anti-HBV therapy and determining if current therapy is adequate to delay liver disease progression in the setting of HIV infection over the long-term. It is critical to continue expanding our understanding of HBV treatment to minimize liver disease in patients receiving HBV-active HAART especially since HAART has been introduced into areas of the world with high HBV endemicity. The first Aim tests the hypothesis that long-term HBV DNA control is better with combination anti- HBV therapy in the HAART regimen. We will be well-poised to contribute meaningful data to this controversial area since we will follow subjects for a minimum of 10 years. We will test HBV DNA and other HBV laboratory markers at 6-month intervals to determine which anti-HBV regimen is best able to suppress HBV DNA with extended therapy. We will examine HBV viral and HIV-related factors associated with HBV DNA suppression as well as addressing the emergence of drug-resistant HBV with extended anti-HBV therapy. We will look for novel drug-resistant HBV mutations in the setting of long-term tenofovir. The second Aim will test the hypothesis that maintaining HBV DNA suppression using potent anti-HBV active agents with a high genetic barrier to resistance will halt the progression of liver disease, which is the goal of therapy, or even improve liver disease. We will use a novel non- invasive marker to prospectively assess liver disease for this Aim. The third Aim uses a novel technique in the HBV field to determine at what HBV DNA level HBV evolution is unlikely to occur while on HBV treatment. This is a critical issue since this threshold HBV DNA level would then become the treatment goal. Lastly, this cohort is the largest, prospectively-followed HIV-HBV co- infection cohort worldwide so will also serve as a platform for future virological, immunological, and clinical questions regarding HIV-HBV co-infection.